The Impact of BRCA Testing: Research at ASCO and Treatment Implications for Ovarian, Breast, Prostate, and Pancreatic Cancers

By Julie A. Katz, M.P.H., M.Phil.

Introduction

The BRCA gene was featured prominently in research for several solid tumors at the 2015 American Society of Clinical Oncology (ASCO) annual meeting. New data at ASCO 2015 highlighted the clinical implications of BRCA1 and BRCA2 in ovarian, breast, prostate, and pancreatic cancers. These data will continue to feature prominently in clinical decisions around chemotherapy utilization and the development and utilization of PARP inhibitors.

It is well established that germline mutations in BRCA1 and BRCA2 dramatically increase the risk of female breast and ovarian cancers, 54%-84% above the risk of developing these cancers in non-carriers.1 There are a potentially large number of possible different mutants for the two genes. BRCA1, residing on chromosome 17, has a coding region of 5,589 nucleotides; approximately 1,200 different BRCA1 mutations have been reported. BRCA2 resides on chromosome 13 and has a coding region of 10,254 nucleotides; approximately 1,380 different mutations have been reported.2

Epidemiology of BRCA Mutations and Associated Tumor Types

The impact of high penetrant gene mutations in defining clinically relevant patient population sizes will depend on the incidence of the tumor type and the frequency of the BRCA mutation in that particular tumor type (Table 1).

* From the general population. It is estimated to be 16% in Ashkenazi Jewish populations and 19% in persons with familial pancreatic adenocarcinoma.

+ Calculated using the average of the BRCA mutation percentage range estimate.

§ All incidence figures are sourced from CancerMPact® Patient Metrics. Kantar Health. Available at www.cancermpact.com. Accessed June 2, 2015.

Sources various. Compiled by Kantar Health.

Screening and the Importance of Family History

Dr. Karen Lu highlighted the value of BRCA genetic testing and family history for risk assessment and detection of second ovarian or breast cancers and such cancers in relatives. She noted that the benefits of genetic testing in ovarian cancer patients include prognostic information for risk of a second cancer, the prevention of second breast and ovarian cancers, and personalization of treatment. For example, although Lynparza® (olaparib, AstraZeneca) is currently approved for use in ovarian cancer in the absence of biomarker requirement, most current clinical trials evaluating PARP inhibitors require patients to have a mutated BRCA1 or BRCA2 gene.

National Comprehensive Cancer Network (NCCN) and ASCO guidelines recommend the universal BRCA1/BRCA2 testing of ovarian patients and all triple-negative breast cancer patients, particularly if the patient is younger than 60 when diagnosed. The risk of a second primary breast cancer is 17% in BRCA1-positive individuals and 7% in BRCA2-positive individuals.

The risk of being diagnosed with ovarian cancer following treatment for breast cancer is 12.7% in BRCA1 individuals and 6.8% in BRCA2 individuals. Dr. Lu concluded that the absence of information from genetic testing of cancer patients is a missed opportunity for the prevention and early detection of second cancers.

Triple-Negative Breast Cancer and BRCA Screening

Citing Kwon et al., Dr. Lu stated the importance of BRCA testing regardless of family history as few female family members or small families can mask genetics relative to breast and ovarian cancer. While Dr. Lu recommended genetic testing for triple-negative breast cancer patients diagnosed before age 50­ – a population with BRCA mutation frequency of 17.5% – she also highlighted data showing that the estimated BRCA mutation frequency of individuals with any type of breast cancer diagnosed before age 40 is 11%.

Given the high incidence of breast cancer, these data raise the issue of eligibility in PARP inhibitor clinical trials, a current debate in the field. Given the many emerging treatment options for BRCA mutation carriers including all BRCA-mutated breast cancer patients in PARP inhibitor trials could represent many more treatment and research opportunities down the road.

BRCA1/BRCA2 Screening in Prostate Cancer

In a presentation on treatment of BRCA mutation carriers, Dr. Judy Garber reported data showing the risk of prostate cancer to be between 4% and 20% for BRCA1 carriers and between 20% and 34% for BRCA2 mutation carriers. This is a low cancer risk compared with the risk in BRCA1 mutation carriers of female breast cancer (54%-84%) and of ovarian cancer (40%-60%).

The risk is similar to that of ovarian cancer for carriers of BRCA2 mutations (15%-20%). The PSA test carries a high sensitivity (>90%), but a low specificity to detect prostate cancer. It also detects benign prostatic hyperplasia (BPH) as well as low-risk, localized disease that may not require treatment. Dr. Garber pointed out that the benefits of PSA screening in an unselected male population do not seem to outweigh the harm due to complications (such as impotence or incontinence) from treating these low-risk patients. Therefore, she suggested the data are insufficient to recommend PSA screening in the general population.

Data presented on PSA screening in the BRCA mutation carrier population, however, tell a different story. The ongoing IMPACT study (NCT00261456) is evaluating PSA screening in BRCA mutation carriers. In this study of 2,481 patients aged 40 to 69 years old, 1,522 of whom are BRCA mutation carriers, PSA screening with a threshold of >3.0 ng/dL was significantly more accurate at identifying prostate cancer among BRCA2 mutation carriers than in non-carriers.3

The BRCA2 mutation carriers had a higher risk of disease than the non-carriers. Because the positive predictive value of the PSA test (the probability that subjects with a positive screening test truly have the disease) increases as the prevalence increases, it is not surprising that the PSA test has more accuracy (higher positive predictive value) as the prevalence of prostate cancer in the tested population increases.

The current NCCN guidelines reflect this elevated prostate cancer risk in BRCA1 and BRCA2 mutation carriers. They recommend that BRCA2 mutation carriers begin prostate cancer screening at 40 years old and that BRCA1 mutation carriers may consider prostate cancer screening beginning at 40 years old. Putting these guidelines into practice will identify prostate cancers among a high-risk population, lead to early detection, and create more treatment opportunities for these BRCA mutation carriers.

BRCA Mutations and Prostate Cancer Prognosis

More new data presented at ASCO showed that not only do BRCA mutations carry significant increased risk of prostate cancer for men 65 or younger and a significant lifetime risk, they also have prognostic implications. Prostate cancers in BRCA1 and BRCA2 mutation carriers are more likely to have lymph node involvement, higher Gleason scores, and distant metastases than non-carriers.4

A study of 1,302 men with localized prostate cancer and 67 men with BRCA1 or BRCA2 mutations showed that BRCA1 and BRCA2 mutation carriers had worse three-, five-, and 10-year overall survival.5

In a study of 1,904 prostate cancer cases, identified from 4,187 men undergoing prostate biopsy for an abnormal screening test, the 12-year prostate cancer-specific survival among BRCA2 non-carriers was higher (94.3%) compared with men with BRCA2 mutations (61.8%).6

This poorer prognostic profile among BRCA mutation carriers makes additional screening for BRCA mutation carriers even more important to detect their cancers as early as possible. This prognostic profile also will have possible implications for the differential treatment of BRCA mutation carrier prostate cancers.

Pancreatic Cancer Screening

Several PARP inhibitor clinical trials are currently enrolling pancreatic cancer patients, and some trials are enrolling only patients with BRCA mutations. However, the NCCN has no current guidelines on BRCA mutation screening in the pancreatic patient population. Dr. Garber noted that this is attributable to the fact that the influence of family history of BRCA in pancreatic cancer is not established. Moreover, while screening could detect more cancers earlier, it is not sufficient for a screening study to show the detection of more cancers; it must also show a survival benefit.

To date, no data show a survival benefit of screening. Unlike the higher likelihood of a BRCA mutation in a younger age of diagnosis with ovarian, breast, and prostate cancers, Dr. Garber pointed out that no age effect has been evident in pancreatic cancer.

There are reasons for and against screening for pancreatic cancer. Reasons to screen high-risk individuals include the availability of surgical options for the treatment of early pancreatic cancer and that a high percentage of pancreatic cancer patients are diagnosed at advanced stages. On the other hand, disadvantages to screening include low sensitivity of potential screening modalities to identify cases and false positives which can lead to unnecessary biopsies and high-risk pancreatic resections.

Pancreatic Screening Guidelines

Current pancreas cancer screening guidelines are based on the 2012 International Cancer of the Pancreas Screening (CAPS) Consortium Statements:

BRCA2 mutation carriers with two or more relatives with pancreatic cancer should consider screening

No consensus exists on whether BRCA1 mutation carriers with a family history of pancreatic cancer should consider screening

No consensus exists on whether BRCA2 mutation carriers without a family history of pancreatic cancer should consider screening

In a BRCA1 and BRCA2 screening study, 306 unselected, consecutive, incident patients with pancreatic ductal adenocarcinoma were recruited at a single cancer center over a two-year period. The study found 14 patients (4.6%) with a BRCA mutation, 11 patients with BRCA2 mutation and three patients with a BRCA1 mutation.7 (The majority of BRCA mutation-positive patients did not have a family history of cancer that met genetic testing criteria [NCCN or the Ontario Ministry of Health and Long-Term Care criteria]). This study supports broader screening of BRCA genetic testing for increased detection; patients without a family history of pancreatic cancer should still consider screening.

Genetic Panel Testing

In addition to BRCA mutations, there are several high-penetrant cancer susceptibility genes in common cancers (Table 2).

Mutations of these high-penetrant genes are generally characterized by young age of onset, multiple family members with cancer, and multiple cancers in one family member. Dr. Lu pointed out that the plethora of high-penetrant cancer susceptibility genes suggests the benefit of panel testing.

Panel testing can identify cancer types that are not frequently associated with mutations, such as BRCA1 in gastric cancer and MYH in breast cancer.10 Panel testing can also identify more genes associated with certain cancers; however, there are some concerns, including physician understanding of moderate penetrant genes and variants of uncertain significance, patient understanding of the testing results, and potential patient harm. For instance, the NCCN guidelines for the management of women with moderate penetrant genes include risk-reducing salpingo-oophorectomy and risk-reducing mastectomy.

Treatment Implications – Variations in Impact of BRCA mutations

Dr. Stan Kaye’s presentation, “Chemotherapy for BRCA Mutation Carriers: Same but Different?” pointed out that platinum sensitivity and improved survival are the hallmarks of BRCA-mutated ovarian cancer. However, while platinum is more active in BRCA-mutated patients than in non-carrier patients, Dr. Kaye emphasized that the impact of the BRCA mutation is not uniform. For instance, BRCA2 mutations carry a better prognosis than BRCA1 mutations. BRCA1 C61G mutation is associated with a poor response to platinum.

A separate poster presented at ASCO found that BRCA1 promoter methylation does not confer an improved survival.11 Dr. Kaye concluded his presentation by stating that further work is necessary to link the precise BRCA1 and BRCA2 mutation genotype to the clinical phenotype by focusing on treatment outcomes.

Conclusion

BRCA mutation screening policy and practice have important implications for BRCA mutation carriers and their family members. BRCA testing represents an opportunity for early detection or even prevention of cancers. It will affect the ability to identify patient populations eligible for tailored chemotherapeutic and targeted treatment.

Research at ASCO showed that utilizing other screening tests, such as PSA testing and imaging, in a BRCA population can be very effective for detecting cancers with improved accuracy compared with screening in the general population. Further research is needed to understand the variability of clinical outcomes among different genotypes of BRCA mutations.

In many solid tumors, the BRCA gene mutation will likely be a deciding factor in the patient populations eligible for PARP inhibitors and chemotherapy clinical trials. The identification of patients with BRCA mutations will continue to be critical to the ability to provide targeted therapy safely and effectively.

About the Contributor

Julie A. Katz, M.P.H., M.Phil., is a Consultant, in Clinical and Scientific Assessment at Kantar Health.

Kantar Health is a leading global healthcare advisory firm and trusted advisor to the world’s largest pharmaceutical, biotech, and medical device and diagnostic companies. It combines evidence-based research capabilities with deep scientific, therapeutic and clinical knowledge, commercial development know-how, and marketing expertise to help clients launch products and differentiate their brands in the marketplace.

One of Kantar Health’s oncology-related offers is Oncology Market Access US (OMA US), which provides strategic and tactical insights into the evolving oncology landscape. Combining Kantar Health’s commercial and clinical expertise in oncology, OMA US provides cutting-edge information and analysis on critical reimbursement, coverage and competitive issues in the U.S. oncology marketplace.

Kantar Health’s oncology-related offers include CancerMPact® Biomarker Analysis which is a global resource based on a thorough review of literature and recently published data that discusses the current and evolving oncology landscape with regard to biomarker segmentation and geographic, survival, ethnic, racial and gender differences. CancerMPact® Biomarker Analysis is part of the Patient Metrics module – Kantar Health’s best-in-class cancer epidemiology and proprietary patient calculations for target markets.